Examining the Impact of Sirolimus on Ketamine's Antidepressant Effects

Yale University

Status and phase: Completed; Phase 2

Conditions: Depression

Treatments: Drug: Placebo; Drug: sirolimus; Drug: Ketamine

Study type: Interventional

Funder types: Other

Identifiers

NCT02487485

1504015604

Details and patient eligibility

About

The aim of the study is to provide insight into the impact of the immunosuppressant drug sirolimus, on the antidepressant effects of the prototypal rapid-acting antidepressant medication, ketamine.

Full description

This is a double blind, placebo-controlled, crossover, randomized controlled trial investigating the impact of sirolimus on ketamine's antidepressant effects in participants with antidepressant-resistant depressive symptoms.

Prior to this, there was a phase 1 which included monitoring 3 subjects over the course of 7 days after a single dose of sirolimus and ketamine in order to inquire about side effects or interaction effects.

Enrollment: 23 patients

Sex: All

Ages: 21 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Veterans and non-Veterans between the ages of 21-65.
2. Diagnosis of Major Depressive Episode (unipolar or bipolar) as determined by the Mini International Neuropsychiatric Interview (MINI).
3. Antidepressant-resistant depressive symptoms, defined by a history of failure of one or more adequate antidepressant trials.
4. Stable doses of antidepressants (if prescribed) for a period of four weeks or longer at the time of randomization, except for MAOIs which are prohibited.
5. Stable course of psychotherapy (if engaged in) for a period of four weeks or longer at the time of randomization.
6. Females will be included if they are not pregnant or breastfeeding and agree to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile. For those women who are taking an oral contraceptive, we will also ask that they use (or ask their partners to use) a barrier method contraceptive.
7. Able to provide written informed consent according to VA HSS guidelines.
8. Ability to read and write in English.
9. A score greater than or equal to 18 on the Montgomery Åsberg Depression Rating Scale (MADRS).

Exclusion criteria

1. Subjects with a diagnostic history of schizophrenia or schizoaffective disorder, or currently exhibiting manic or mixed episodes or psychotic features as confirmed by the Mini International Neuropsychiatric Inventory.
2. Current, ongoing serious suicidal risk as assessed by evaluating investigator or by scoring 5 or more on the item-10 of the MADRS.
3. Patients with unstable or inadequately controlled medical conditions.
4. Patient requiring prohibited medication.
5. Patient with history of organ transplant.
6. Meet criteria for a diagnosis of substance dependence (amphetamines, cocaine, hallucinogens, inhalants, opioids, sedatives/hypnotics/anxiolytics) within the three months prior to screening date.
7. Positive urine drug screen for cannabis, cocaine, PCP, or barbiturates.
8. Positive pregnancy test at screening at any screen given during the study.
9. Known sensitivity to sirolimus or ketamine.
10. History of sensitivity to heparin or heparin-induced thrombocytopenia.
11. Resting blood pressure lower than 85/55 or higher than 150/95, or resting heart rate lower than 45/min or higher than 100/min.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Triple Blind

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23 participants in 2 patient groups, including a placebo group

ketamine + sirolimus (placebo at time 2)

Experimental group

Description:

Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg orally. After two weeks, they will recieve another infusion of ketamine, and a single dose of placebo.

Treatment:

Drug: Placebo

Drug: sirolimus

Drug: Ketamine

ketamine + placebo (sirolimus at time 2)

Placebo Comparator group

Description:

Participants will be treated twice with ketamine 0.5 mg/kg infused over 40 minutes, combined with a single dose of sirolimus 6 mg placebo. After two weeks, they will recieve another infusion of ketamine, and a single dose of sirolimus 6 mg.

Treatment:

Drug: Placebo

Drug: sirolimus

Drug: Ketamine